Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

Ko, Hyun-Mi; Oh, So-Young; Bang, Hwa-Suk; Kang, Nam-In; Cho, Baik-Hwan; Im, Suhn-Young; Lee, Hern-Ku

doi:10.4049/jimmunol.0900043

Cited by 34 publications

(59 citation statements)

References 48 publications

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“…It was found that propofol could effectively inhibit inflammation caused by endotoxin. Serum levels of inflammatory factors such as IL-6 and TNF-a were significantly decreased upon propofol treatment (Ko et al, 2009;Hammer et al, 2010). Further cell experiments also suggested that propofol could stabilize the cell membrane and reduce inflammatory factors secreted by macrophages and T cells released in the inflammation.…”

Section: Discussionmentioning

confidence: 82%

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Wang

Liu

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to determine the effect of etomidate and propofol pretreatment on the expression of glucocorticoid receptor and the prognosis of sepsis. The sepsis rat was used as a model. During glucocorticoid treatment, etomidate and propofol were applied alone or together at different time points. Survival curves, glucocorticoid receptor expression in the rat adrenal cortex, and inflammation levels were determined. The outcome of sepsis in rats was evaluated based on the combined utilization of propofol and etomidate. The results indicated that the combined utilization of propofol and etomidate pretreatment could significantly improve the effects of glucocorticoids on rat sepsis. Etomidate was shown to enhance the expression of the glucocorticoid receptor, while propofol was shown to inhibit the inflammatory response. Etomidate was best used immediately after modeling, whereas propofol was most suitable for use during the peak inflammatory reaction. These results demonstrated that anesthetics had 4741 Propofol and etomidate effects on GR in rats with sepsis ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4740-4748 (2015) the ability to enhance the effect of glucocorticoids in the treatment of sepsis. Etomidate was indicated for use in the early stage of inflammation to enhance expression of the glucocorticoid receptor, while propofol application was indicated at the peak of the inflammatory reaction owing to its strong anti-inflammation effect.

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Section: Discussionmentioning

confidence: 82%

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Wang

Liu

et al. 2015

Genet. Mol. Res.

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“…Clinical trials in human subjects have also demonstrated that Gln treatment decreases infectious complications, shortens hospital stay, and decreases hospital costs in a number of patient populations (18). Regarding the mechanisms, we have shown that Gln inhibits cytosolic phospholipase A 2 (cPLA 2 ) activity (19) by deactivating p38 and JNK MAPKs (20). As a result, Gln exhibits a beneficial effect on murine asthma (21).…”

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confidence: 92%

Glutamine Suppresses Airway Neutrophilia by Blocking Cytosolic Phospholipase A2 via an Induction of MAPK Phosphatase-1

Lee

Kim

et al. 2012

The Journal of Immunology

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Neutrophils are inflammatory cells that may contribute in a crucial way to the pathophysiology of steroid-resistant severe asthma. We previously reported that the nonessential amino acid l-glutamine (Gln) suppressed the recruitment of neutrophils into the airway in a murine model of asthma. In this study, we investigated the mechanisms by which Gln exerts beneficial effects in airway neutrophilia. We used the model we previously developed, which is suitable for examining sequential early asthmatic events, including neutrophil infiltration. Gln suppressed airway neutrophilia in a CXC chemokine-independent way. Airway neutrophilia was associated with cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO) activities. p38 MAPK, the upstream pathway of cPLA2 and 5-LO, played a key role in inducing airway neutrophilia. Gln inhibited not only the phosphorylation of cPLA2 and p38 MAPK but also leukotriene B4 levels in the airways. Gln induced the early induction of MAPK phosphatase-1 (MKP-1) protein, a negative regulator of p38. MKP-1 small interfering RNA abrogated all the effects of Gln. Our results suggest that pathways involving p38/cPLA2/5-LO have a major role in airway neutrophilia. Gln suppresses airway neutrophilia via inhibiting p38 MAPK and its downstream pathways in an MKP-1–dependent way, which may provide a novel therapeutic strategy for pulmonary neutrophilic inflammatory diseases.

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“…Gln was dissolved in sterilized distilled water to 3%. A volume of 0Á5 ml (750 mg/ kg) [12][13][14][15] was administered intraperitoneally (i.p.) 10 min before or 10 min after LPS injection.…”

Section: Reagentsmentioning

confidence: 99%

“…Isolated lung tissues were frozen in liquid nitrogen and stored at 270 C until analysis. Small lung specimens were homogenized in PhosphoSafe Extraction Reagent (Novagen, Madison, WI, USA) and subjected to immunoblotting analysis, as described previously [15].…”

Section: Immunoblotting Analysismentioning

confidence: 99%

“…To decipher the mechanism of Gln inhibition of cPLA 2 , we demonstrated recently that Gln deactivated p38 and Janus kinase (JNK) mitogenactivated protein kinases (MAPKs) by rapidly inducing MAPK phosphatase (MKP)-1 protein [15], which preferentially dephosphorylated p38 and JNK [16,17], suggesting that Gln inhibited cPLA 2 phosphorylation indirectly by blocking the kinase activity of p38, a major upstream pathway for cPLA 2 phosphorylation [18].…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of glutamine inhibition of cytosolic phospholipase a2 (cPLA2): Evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA2

Lee

Kim

Jeong

et al. 2015

Clinical and Experimental Immunology

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SummaryNon-essential amino acid L-glutamine (Gln) possesses anti-inflammatory activity via deactivating cytosolic phospholipase A 2 (cPLA 2 ). We showed previously that Gln deactivated cPLA 2 indirectly via dephosphorylating p38 mitogen-activated protein kinase (MAPK), the major kinase for cPLA 2 phosphorylation, through inducing MAPK phosphatase-1 (MKP-1). In this study, we investigated the precise mechanism underlying Gln deactivation of cPLA 2 . In lipopolysaccharide (LPS)-treated mice, Gln injection resulted in dephosphorylation of phosphorylated cPLA 2 (p-cPLA 2 ), which coincided with rapid Gln induction of MKP-1. MKP-1 small interfering RNA (siRNA) abrogated the ability of Gln to induce MKP-1 as well as the dephosphorylation of cPLA 2 . Co-immunoprecipitation and in-situ proximity ligation assay revealed a physical interaction between MKP-1 and p-cPLA 2 . In a murine model of allergic asthma, we also demonstrated the physical interaction between MKP-1 and p-cPLA 2 . Furthermore, Gln suppressed various allergic asthma phenotypes, such as neutrophil and eosinophil recruitments into the airway, airway levels of T helper type 2 (Th2) cytokines [interleukin (IL)-4, IL-5 and IL-13], airway hyperresponsiveness, mucin production and metabolites (leukotriene B 4 and platelet-activating factor) through inhibiting cPLA 2 in a MKP-1-dependent manner. These data suggest that MKP-1 uses cPLA 2 , in addition to p38, as a substrate, which further potentiates the anti-inflammatory action of Gln.

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Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

Cited by 34 publications

References 48 publications

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Glutamine Suppresses Airway Neutrophilia by Blocking Cytosolic Phospholipase A2 via an Induction of MAPK Phosphatase-1

Mechanism of glutamine inhibition of cytosolic phospholipase a2 (cPLA2): Evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA2

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